Current topics in microbiology and immunology最新文献

To write about dengue retrospective epidemiology is a challenging subject because until laboratory diagnosis tests were developed to confirm human infections by dengue virus (DENV) between 1940 and 1950, all reports about disease or epidemics referred to a generic "dengue/break bone fever/contagious fever/bilious remitting fever." These nomenclatures employed in past times had perspectives based on medical reports, letters and diaries of people living in the affected areas at the time, and local newspaper reports. As Packard (Bull Hist Med 90(2):193-221) highlighted, the difficulty of using historical sources and "the ambiguous nature" of eighteenth-century disease categories turns the analysis puzzling. Nevertheless, if judiciously used, it can illuminate the history of dengue epidemics over time.In this chapter, we will focus on three periods that were pivotal to shaping our current understanding of dengue disease and epidemiology: (1) First reports of a dengue-like disease and the impact of the infection during the seventeenth and eighteenth centuries; (2) The impact of the II World War (II WW) on the spread of the DENV and its vector worldwide; and (3) The re-introduction of dengue in the Americas and the challenge of Public Health services to control the dramatic escalation of cases and the introduction of new serotypes/genotypes. It is worth mentioning that in the last years, South and Central America and Caribe account for more than 80% of dengue cases in the world (PAHO).

Dengue virus (DENV) is a rapidly evolving arbovirus responsible for significant morbidity and mortality worldwide. Understanding its evolutionary trajectory is essential for tracking viral emergence, transmission dynamics, and the factors driving its geographic expansion. This chapter provides a comprehensive overview of the genetic diversification and phylogenetic pathways of DENV, focusing on serotype evolution and the classification of genetic lineages. We discuss molecular phylogenetics as a key tool for elucidating the evolutionary relationships among DENV strains and highlight the application of phylodynamic approaches to infer viral dispersal patterns in endemic and newly affected regions. Furthermore, we examine the historical spread of DENV, with particular attention to cross-border transmission events facilitated by human mobility and trade. Additionally, we explore the role of climatic and ecological drivers, such as temperature fluctuations, vector adaptation, and urbanization, in shaping the evolutionary dynamics of the virus. By integrating genomic, epidemiological, and ecological data, this chapter underscores the importance of a multidisciplinary approach to dengue surveillance and control, ultimately contributing to the refinement of predictive models and public health interventions aimed at mitigating the impact of DENV outbreaks.

Human papillomavirus (HPV) is one of the most common sexually transmitted infections globally, infecting most sexually active individuals. HPV infection is usually asymptomatic and often transient; however, some infections can persist and cause cancer. In fact, HPV is the main cause of cervical cancer and can also cause cancer of the penis, anus, vagina, vulva, mouth, or throat. Fortunately, there are seven approved vaccines available that are highly effective at preventing infection and HPV-associated cancers. Nevertheless, there is still a need for a better understanding of the mechanisms underlying natural and vaccine-elicited immunity to HPV. Immune responses after natural infection or vaccination encompass both humoral and cell-mediated responses. In natural infection, cell-mediated responses are believed to be responsible for the elimination of virus-infected cells. However, many individuals do not appear to seroconvert following infection. Conversely, vaccination elicits long-lasting antibody levels and robust cell-mediated immune memory. Despite the number of publications on HPV infection and prophylactic vaccine responses, many immune mechanisms, as well as the influence of infection site, remain to be elucidated. In addition, there is an increasing interest to understand the potential role of specific effector functions of antibodies and T cell subsets on vaccine-elicited protection-particularly, how these mechanisms may differ with vaccine type, adjuvant, and dosing schedule. Finally, standardization of relevant immune assessments is critical to facilitate comparisons across studies and new vaccine developments.

Epstein-Barr virus is a ubiquitous gammaherpesvirus that usually causes an asymptomatic infection followed by lifelong persistence in memory B cells. Virus replication is controlled by a robust antiviral immune response, and EBV-associated lymphoproliferative diseases only develop in immunocompromised individuals. However, systemic chronic active Epstein-Barr virus (CAEBV) disease occurs in individuals without an apparent immunodeficiency or an underlying genetic immune defect. These individuals cannot control EBV infection, leading to life-threatening conditions including haemophagocytic lymphohistiocytosis, organ failure and malignant lymphomas. CAEBV disease is characterized by systemic inflammation, markedly elevated EBV DNA load in the blood, clonal expansion of EBV-infected T cells and/or NK cells, and multi-organ infiltration by the infected cells. Here we summarize the current understanding of the pathogenesis of systemic CAEBV disease, identifying viral, genetic and immunologic changes that could be integral to disease development and progression, as well as targeted by future precision medicine.

EBNA2 and EBNA-LP are the earliest expressed viral latency proteins following Epstein-Barr virus (EBV) infection of B cells and are essential for cellular transformation and immortalization. Both proteins are co-expressed during latency IIb and III states and exhibit temporal regulation from viral promoters Wp to Cp during the initial 24 h of infection. Recent advances have fundamentally transformed our understanding of EBNA2's mechanisms of action, revealing its ability to undergo liquid-liquid phase separation to form nuclear condensates that reorganize host chromatin topology and create accessible chromatin domains. EBNA2 functions through sophisticated partnerships with cellular transcription factors including RBP-Jκ and EBF1, exploiting preexisting B cell transcriptional networks by targeting super-enhancers and establishing new enhancer-promoter contacts that alter over 1700 chromatin looping interactions genome-wide. The protein's unique structural features, including the virus-specific N-terminal END domain and intrinsically disordered regions critical for phase separation, represent potential therapeutic targets. Importantly, EBNA2 has emerged as a critical factor in autoimmune disease pathogenesis, with specific alleles conferring differential multiple sclerosis risk through binding at autoimmune susceptibility loci. While historically viewed as an EBNA2 coactivator, EBNA-LP has been revealed to have essential EBNA2-independent functions, serving as a key viral antagonist of restriction factors Sp100 and Sp140L to prevent innate antiviral sensing and enable successful viral genome establishment. EBNA-LP regulates chromatin architecture through interactions with YY1 and modulates transcription factor-binding accessibility at cellular genes, while both proteins cooperate at EBV super-enhancers to control target gene networks essential for B cell transformation and survival.

Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and as such, it has been intensively pursued as a therapeutic target. Despite the high frequency of AKT activation in human tumors, the clinical performance of AKT inhibitors remained largely disappointing for many years. However, the recent approval of the AKT inhibitor capivasertib (formerly AZD-5363) for the treatment of breast cancer provides clinical validation of its therapeutic relevance and raises the possibility that AKT inhibitors could still provide clinical benefit either as monotherapy in patients with the rare AKT-E17K mutation or in broader patient populations when combined with other agents. In this chapter, we review the evidence for AKT dependence in human tumors, the importance of genetic and cellular context in AKT dependence, and the challenges of translating AKT inhibition into therapeutic benefit.

Epstein-Barr virus (EBV) is a potent oncogenic virus capable of manipulating cell death and cell survival pathways in order to persist in human B cells. Since the discovery of EBV in Burkitt's lymphoma cells in 1964, cell culture has played an important role in uncovering EBV's ability to overcome cell death pathways such as apoptosis and ferroptosis. Whilst apoptosis is a genetically defined and developmentally regulated non-immunogenic cell death program, ferroptosis is a mode of necrotic cell death that is closely linked to amino acid, lipid, redox, energy, selenium, and iron metabolism. Such cell culture studies have not only played a pivotal role in our understanding of the role of EBV in growth transformation and cancer but have also enriched knowledge in the fields of cell death. Artificial in vitro cell culture conditions including (i) oxygen partial pressure, (ii) media composition, (iii) cell density, (iv) cell-, and (v) pH-homo- versus heterogeneity have profound effects on cell growth and responses to death stimuli. In fact, a search for pro-survival genes in Burkitt's lymphoma cells plated at low cell density in FCS-supplemented RPMI 1640 medium had revealed two genes, glutathione peroxidase-4 (GPX4) and ferroptosis-suppressor protein-1 (FSP1), that are now well-known master regulators protecting cells from ferroptosis. Here we review those early fundamental studies and reflect on the subsequent literature that seeks to understand how EBV viral products can modulate cellular pathways during transformation and oncogenesis, reducing the requirement for mutations in cellular genes that are found more commonly in EBV-negative Burkitt's lymphomas.

Cell migration is an enormously complex process that requires sophisticated regulation and exquisite coordination of many cellular proteins that must act in a temporally and spatially orchestrated manner to achieve directional motion. Much like neuromuscular control of gait and walking, except within a single cell, a series of rapid feedback mechanisms must act in a cyclical manner to result in movement. The protein-serine kinase Akt/PKB that acts downstream of phosphatidylinositol 3' kinase (PI3K) activation is intricately involved in normal cell migration and in aberrant movement (e.g., cancer metastasis), but its role can be either pro- or anti-migration depending on cellular context. These contradictory effects likely reflect the nature of cellular motion, in that perturbations that disturb the continuity or integrity of migratory machines tend to be inhibitory. In contrast, increasing overall efficiency/coordination of the processes results in greater mobility. The net result of modulating Akt/PKB is therefore highly dependent upon other inputs into the cell and their context. Here, we briefly describe the molecular events associated with cellular migration, then describe current knowledge of Akt/PKB targets involved in this process, and conclude by discussing implications for suppression of cancer dissemination.

Burkitt lymphoma (BL) remains a prevalent pediatric cancer in sub-Saharan Africa and was the first human cancer identified with a virus when Epstein-Barr virus (EBV) was discovered in a Ugandan BL tumor in 1964. The impact of EBV in BL is highlighted by a new molecular tumor classification of EBV positivity versus negativity which is starting to supersede longstanding epidemiologic classifications. The high incidence of EBV-positive BL in Africa and Papua New Guinea has been linked to Plasmodium falciparum (Pf) malaria coinfections in young children. Epidemiologic studies have yielded insight into early-age EBV infections and have demonstrated direct impacts of Pf malaria infections on EBV reactivation and disruptions in EBV persistence. Moreover, when children residing in malaria holoendemic regions are contending with chronic Pf malaria infections, they undergo immune adaptations to mitigate life-threatening immunopathology. We postulate that this malaria-induced immune conditioning leads to diminished EBV-specific cellular immune surveillance, when combined with higher B cell proliferation, and EBV load creates a permissive environment for BL tumorigenesis.